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Flashcards in Adipose Shore Deck (28)
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1

What is cortisols effect on mature adipocytes?

Causes an increase in Adipose Triglyceride Lipase (ATGL) which results in increased lipolysis leading to increased FFA

2

What is cortisols effect on preadipocytes?

Leads to differentiation and accumulation of more adipocytes, resulting in increased visceral adipose depots and central obesity.

3

What can cortisol ultimately lead to?

Insulin resistance and type II diabetes.

4

What is 11β HSD1?

- reduces cortisone to cortisol, activating it.
- thought to be the activity that makes you FAT
- requires NADPH which it gets from hexose-5-phosphate dehydrogenase
- found in the liver and adipose tissue
- causes local increase in cortisol leading to increased central adipose deposits (preadipocytes) and increased lipolysis (when acting on mature adipocytes)

5

What disease in 11β HSD1 thought to be involved in?

thought to contribute to the phenotype of central adipose depots in hypercortisolemia

6

What is 11β HSD2?

- Oxidizes cortisol to cortisone, inactivating it
- Found in the kidney
- located on ER membrane with catalytic domain facing inward

7

What is the relationship between 11β HSD1 activity and its location in either the liver or adipose tissues and BMI?

Liver: As BMI increases, 11β HSD1 activity decreases (lower systemic cortisol levels and less gluconeogenesis)
Adipose: As BMI increases, 11β HSD1 activity increases leading to increased central depots and increased systemic FFA levels

8

What is the relationship between 11β HSD1 in obese women?

Increased 11β HSD1 correlated with increased adipocytes, decreased adiponectin, increased lipolysis, and increased insulin resistance

9

What did the study with monozygotic twins show?

- Twins with the same BMI had the same levels of 11β HSD1 expression.
- If twin had higher BMI, they had more expression of 11β HSD1 in subcutaneous fat and therefore increased fat and increased insulin resistance

10

How does one develop type II diabetes?

increased adipose leads to increased inflammation leading to increased cortisol to lessen the inflammation. Increased cortisol increases gluconeogenesis and leads to increased insulin resistance and β cell dysfunction. So combo of obesity (increased adipose) and increased cortisol leads to development of diabetes 2

11

What are the levels of 11β HSD1 in obese people?

pretty high

12

What are the effects of cortisol on liver, adipose, and skeletal muscle?

liver- increased gluconeogenesis, insulin unable to suppress glucose release
skeletal muscle- insulin is unable cause uptake of glucose from the blood
adipose- blocks insulins ability to prevent release of FFA to the blood

13

What is one thought on how to combat type II diabetes and hyperlipidemia?

an 11β HSD1 inhibitor like INCB13739 is thought to be able to reverse insulin resistance and the common effects of hypercortisolemia.

14

How does the 11β HSD1 inhibitor work and what are the results?

- it inhibits normal functions of 11β HSD1 thus lowers cortisol levels and decreases fat deposits and insulin resistance, while maintaining normal basal systemic cortisol levels.

- saw improved glycemic control, insulin sensitivity and total cholesterol

15

In the study where the 11β HSD1 inhibitor was used in combo with metformin, what were the results of hormone levels in the blood?

- since 11β HSD1 was inhibited, had lower levels of cortisol thus less negative feedback. This leads to a REVERSIBLE dose-dependednt increase in ACTH.
- Also saw an increase in DHEAS suggesting that DHEA actually is somewhat dependent of ACTH feedback.
- cortisol, aldsoterone and renin levels remained normal.

16

Where do WAT and BAT come from?

mesenchymal stem cells into early lipoblasts then differentiate into white and brown adipose

17

What are the master regulators of WAT differentiation?

PPAR is the nuclear receptor that heterodimerizes with RXR and leads to target gene adiponectin.

18

What is adiponectin?

the target gene of PPAR and is thought to be involved in insulin sensitivity.
*levels are low in obese people

19

What are the master regulators of BAT differentiation?

- PRDMI and PGC1 are transactivation proteins involved in coactivation of PPAR.
- UCP important in thermogenesis in BAT

20

What are the characteristics of WAT vs BAT?

WAT: direct and indirect (catecholamines) innervation, side off nucleus, single large lipid droplet
BAT: direct sympathetics, central nucleus, mitochondria, expression of D2 and UCP1 (mt)

21

What is PPAR gamma?

peroxisome proliferator-activated receptor.
- ligand-dependent nuclear TF that binds to PPAR-Response elements in promotor and is absolutely necessary for both WAT and BAT formation.
- increases expression of adiponenctin thus increases insulin sensitivity (decreases negative effectors)
- TZD is a ligand that increases insulin sensitivity

22

What are the effects of PPAR gamma in WAT?

positive effects: increases adiponectin and enhances glucose uptake and FFA uptake so less in circulation
negatives: causes increase in sc WAT, patients don't normally want to get fat

23

What is the role of selective receptor modulators and insulin resistance?

- TZD can lead to increased insulin sensitivity but also causes deleterious side effects
- SRMs can bind to a separate allosteric site and results in increased insulin sensitivity along with fewer side effects because some of the corepressors are able to remain attached preventing expression of the side effects.

24

What type of thermogenesis is BAT involved in?

Non-shivering thermogenesis. Will see increased activation when in cold environment.

25

What are levels of BAT like between thin and obese individuals?

high levels in lean and small levels in obese.

26

Where is BAT most found?

supra-clavicular, anterior cervical, costovertebral, mediastinal then axillary

27

What is the relationship of BAT to sex, age, BMI and glucose levels?

- More BAT in women than men, but both show increased activity in colder temperatures.
- BAT decreases as age increases
- BAT decreases as BMI increases
- BAT decreases as glucose increases

28

Describe the pathway of thermogenesis generation in BAT

1. NE stimulates β-adrenergic receptors
2. increased cAMP which activation hormone sensitive lips and induces expression of D2.
3. D2 increases conversion of T4-->T3
4. T3 binds to the TRE in the promotor region leading to expression of UCP1
5. get uncoupling during ATP generation, so instead of ATP release a proton is released and heat is the product

** can be used as a mechanism to reduce fat!!